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Delays in time to treatment initiation (TTI) for new cancer diagnoses cause patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of increased TTI and association with overall survival. We utilized prospective data from the National Cancer Database for newly diagnosed United States patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004-13. TTI was defined as days from diagnosis to first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (N = 363,863), renal (N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 to 29 days (P<0.001). Aside from year of diagnosis, determinants of increased TTI included care at academic center, race, education, prior history of cancer, transfer of facility, comorbidities and age. Increased TTI was associated with worsened survival for stages I and II breast, lung, renal and pancreas cancers, and stage I colorectal cancers, with hazard ratios ranging from 1.005 (95% confidence intervals [CI] 1.002-1.008) to 1.030 (95% CI 1.025-1.035) per week of increased TTI. TTI has lengthened significantly and is associated with absolute increased risk of mortality ranging from 1.2-3.2% per week in curative settings such as early-stage breast, lung, renal and pancreas cancers. Studies of interventions to ease navigation and reduce barriers are warranted to diminish potential harm to patients.

Despite the industrial implications and worldwide abundance of gas hydrates, the formation mechanism of these compounds remains poorly understood. We report direct molecular dynamics simulations of the spontaneous nucleation and growth of methane hydrate. The multiple-microsecond trajectories offer detailed insight into the process of hydrate nucleation. Cooperative organization is observed to lead to methane adsorption onto planar faces of water and the fluctuating formation and dissociation of early hydrate cages. The early cages are mostly face-sharing partial small cages, favoring structure II; however, larger cages subsequently appear as a result of steric constraints and thermodynamic preference for the structure I phase. The resulting structure after nucleation and growth is a combination of the two dominant types of hydrate crystals (structure I and structure II), which are linked by uncommon 5¹²6³ cages that facilitate structure coexistence without an energetically unfavorable interface.

Endoscopic ultrasound (EUS) and hormone-stimulated pancreatic function tests are considered useful, and possibly complementary, in the diagnosis of early chronic pancreatitis (CP). Few past studies have compared either methods with a histological gold standard. The aims were to assess correlations of EUS score and endoscopic pancreatic function test (ePFT) results with the degree of histological fibrosis, as well as the sensitivity of each method for detecting fibrosis. This was a retrospective study of patients who underwent EUS, ePFT, or both within 12 months of pancreatic resection or wedge biopsy. EUS scoring was performed using 9 standard criteria, with ≥4 considered abnormal. An ePFT peak bicarbonate concentration <80 mM was considered abnormal. Surgical specimens were reviewed in a blinded manner by an expert pancreatic pathologist and assigned a fibrosis score from 0 to 12. Correlations of the EUS score and ePFT peak bicarbonate with the fibrosis score are reported using the Spearman correlation coefficient. Sensitivity and specificity was calculated for each method against the histological gold standard (fibrosis score ≥2). Twenty-five patients were included. The fibrosis score significantly correlated with the EUS score (r=0.72; 95% confidence interval (CI)=0.43, 0.87; P<0.001) and the ePFT peak bicarbonate (r=-0.57; 95% CI=-0.81, -0.10; P=0.016). EUS had a sensitivity of 84% (95% CI=69, 100) and specificity of 100% (95% CI=40, 100) compared with histology. The ePFT had a sensitivity of 86% (95% CI=67, 100) and specificity of 67% (95% CI=13, 100). When both modalities were combined, the sensitivity increased to 100% (95% CI=63, 100). Both EUS and ePFT are useful tests in the diagnosis of CP. Combining EUS with ePFT may improve the sensitivity for detection of early fibrosis.

Species that coexist in diverse natural communities interact in complex ways that alter each other’s abundances and affect selection on each other’s traits. Consequently, predicting trait evolution in natural communities may require understanding ecological and evolutionary dynamics involving a number of species. In August 2016, the American Society of Naturalists sponsored a symposium to explore evolution in a community context, focusing on microevolutionary processes. Here we provide an introduction to our perspectives on this topic by defining the context and describing some examples of when and how microevolutionary responses to multiple species may differ from evolution in isolation or in two-species communities. We find that indirect ecological and evolutionary effects can result in nonadditive selection and evolution that cannot be predicted from pairwise interactions. Genetic correlations of ecological traits in one species can alter trait evolution and adaptation as well as the abundances of other species. In general, evolution in multispecies communities can change ecological interactions, which then feed back to future evolutionary changes in ways that depend on these indirect effects. We suggest avenues for future research in this field, including determining the circumstances under which pairwise evolution does not adequately describe evolutionary trajectories.

Much work has shown that the environment can induce non-genetic changes in phenotype that span multiple generations. Theory predicts that predictable environmental variation selects for both increased within- and across-generation responses. Yet, to the best of our knowledge, there are no empirical tests of this prediction. We explored the relationship between within- versus across-generation plasticity by evaluating the influence of predator cues on the life-history traits of Daphnia ambigua. We measured the duration of predator-induced transgenerational effects, determined when transgenerational responses are induced, and quantified the cues that activate transgenerational plasticity. We show that predator exposure during embryonic development causes earlier maturation and increased reproductive output. Such effects are detectable two generations removed from predator exposure and are similar in magnitude in response to exposure to cues emitted by injured conspecifics. Moreover, all experimental contexts and traits yielded a negative correlation between within- versus across-generation responses. That is, responses to predator cues within- and across-generations were opposite in sign and magnitude. Although many models address transgenerational plasticity, none of them explain this apparent negative relationship between within- and across-generation plasticities. Our results highlight the need to refine the theory of transgenerational plasticity.

Environmental signals can induce phenotypic changes that span multiple generations. Along with phenotypic responses that occur during development (i.e. ‘within-generation’ plasticity), such ‘transgenerational plasticity’ (TGP) has been documented in a diverse array of taxa spanning many environmental perturbations. New theory predicts that temporal stability is a key driver of the evolution of TGP. We tested this prediction using natural populations of zooplankton from lakes in Connecticut that span a large gradient in the temporal dynamics of predator-induced mortality. We reared more than 120 clones of Daphnia ambigua from nine lakes for multiple generations in the presence/absence of predator cues. We found that temporal variation in mortality selects for within-generation plasticity while consistently strong (or weak) mortality selects for increased TGP. Such results provide us the first evidence for local adaptation in TGP and argue that divergent ecological conditions select for phenotypic responses within and across generations.

Disordered hemostasis associated with life-threatening hemorrhage commonly afflicts patients in the emergency department, critical care unit, and perioperative settings. Rapid and sensitive hemostasis phenotyping is needed to guide administration of blood components and hemostatic adjuncts to reverse aberrant hemostasis. Here, we report the use of resonant acoustic rheometry (RAR), a technique that quantifies the viscoelastic properties of soft biomaterials, for assessing plasma coagulation in a cohort of 38 bleeding patients admitted to the hospital. RAR captured the dynamic characteristics of plasma coagulation that were dependent on coagulation activators or reagent conditions. RAR coagulation parameters correlated with TEG reaction time and TEG functional fibrinogen, especially when stratified by comorbidities. A quadratic classifier trained on selective RAR parameters predicted transfusion of fresh frozen plasma and cryoprecipitate with modest to high overall accuracy. While these results demonstrate the feasibility of RAR for plasma coagulation and utility of a machine learning model, the relative small number of patients, especially the small number of patients who received transfusion, is a limitation of this study. Further studies are need to test a larger number of patients to further validate the capability of RAR as a cost-effective and sensitive hemostasis assay to obtain quantitative data to guide clinical-decision making in managing severely hemorrhaging patients.

Background Pancreas-sparing duodenectomy (PSD) offers definitive therapy for duodenal polyposis associated with familial adenomatous polyposis (FAP). We reviewed the long-term complications of PSD and evaluated the incidence of high-grade dysplasia (HGD) and cancer in the remaining upper gastrointestinal tract. Methods Forty-seven FAP patients with duodenal polyposis undergoing PSD from 1992 to 2019 were reviewed. Long-term was defined as > 30 days from PSD. Results All patients were treated with an open technique, and 43 (91.5%) had Spigelman stage III or IV duodenal polyposis. Median follow-up was 107 months (IQR, 26–147). There was no 90-day mortality. Seven patients died at a median of 10.5 years (IQR, 5.4–13.3) after PSD, with one attributed to gastric cancer. Pancreatitis occurred in 10 patients (21.3%), and two required surgical intervention. Seven patients (14.9%) developed an incisional hernia, and all underwent definitive repair. Forty-one patients (87.2%) had postoperative surveillance endoscopy over a median follow-up of 111 months (IQR, 42–138). Three patients (6.4%) developed adenocarcinoma (two gastric, one jejunal), and four (8.5%) had adenomas with HGD (two gastric, two jejunal) with a median of 15 years (IQR, 9–16) from PSD. One patient with gastric adenocarcinoma and all patients with HGD or adenocarcinoma of the jejunum required surgical intervention. Conclusion PSD can be performed with a low but definable risk of long-term morbidity. Risk of gastric and jejunal carcinoma rarely occurs and was diagnosed decades after PSD. This demonstrates the need for lifelong endoscopic surveillance and educates us on the risk of carcinoma in the remaining gastrointestinal tract.